Forward chemical genetics is an emerging field that offers powerful tools to search for novel drug candidates and their targets (Lokey et al., 2002; Specht et al., 2002; Schreiber et al., 2003). Chemical genetics differs from classical genetics by substituting small molecules for mutation inducing agents or X-ray irradiation. Using combinatorial techniques (Jung, 1999; Nicolaou et al., 2002), one can rapidly screen a large number of small molecules and identify those that induce a novel phenotype in a cellular or embryonic system. Once a phenotype effect is found, the next step is to identify the biological target using an affinity matrix made of the immobilized hit compound. However, the synthesis of an efficient affinity matrix in which the hit compound does not lose activity has been shown to be challenging or sometimes totally impossible, because of the difficulties of attaching an adequate linker.
Traditionally, selected and modified active molecules, after biological screening, are fitted with a linker to provide for an attachment point to an affinity bead. In many cases, this can lead to loss of activity and thus a time consuming and laborious structure-activity relationship study (SAR) is required.